RING finger protein (RNF) 183 is a kidney-specific ubiquitin ligase. The kidney is the only tissue that is constantly exposed to hypertonic conditions. For adaptation to hypertonic conditions, nuclear factor of activated T cells 5 (NFAT5), a transcription factor, is essential. We elucidated that the expression of RNF183 is induced by NFAT5. Additionally, we identified ion transporters, Na, K-ATPase and NKCC1, as the substrates of RNF183.These ubiquitinated ion transporters are promoted lysosomal degradation. When cells are exposed to hypertonic stress, short-term adaptation that maintains cell volume leads to a rapid influx of electrolytes via various transporters, and long-term adaptation to hypertonic conditions involves the replacement of ionic osmolytes to uncharged small organic osmolytes. Our data suggests that RNF183 plays a role in downregulating dispensable ion transporters in long-term adaptation.
Recent study has reported that the expression of RNF183 is up-regulated in the colon of inflammatory bowel disease (IBD) patients. We showed that dextran sulphate sodium (DSS)-treated mice induced the expression of Rnf183 and colitis, however, Rnf183 knockout mice was suppressed DSS-induced colitis. Therefore, we consider there is a possibility that the inhibitor of RNF183 become a therapeutic drug of IBD.